Patients infected with Human Immunodeficiency Virus (HIV) experience a variable but progressive decline in immune function resulting in clinically apparent opportunistic infections and other diseases. (Crowe et al., J. Acquir. Immune Defic. Syndr. 4:770-76, 1991; Moss et al., AIDS 3:55-61, 1989). The onset of severe immunodeficiency in HIV-infected individuals is generally accompanied by a marked increase in viral burden and a dramatic decline in circulating CD4.sup.+ T-lymphocytes. Recent approaches to HIV therapy include administration of immunomodulatory agents, such as interleukin-2, with antiretroviral drugs to improve host immunity, thereby attempting to decrease opportunistic infections and prolong survival. Cytokines and growth factors may have a beneficial effect by increasing the number and function of immune system effector cells, including neutrophils, monocytes, macrophages, lymphocytes, dendritic cells, and natural killer cells; however, there is some concern that activation of lymphocytes or monocytes/macrophages may potentially increase the HIV load and produce toxicity that limits the use of these biologics. Indeed, decrease in viral burden is one of the primary clinical end-points for halting the progression of HIV infection. Accordingly, a decrease in viral load is generally regarded as an indicator of efficacy for anti-HIV drugs.
Inhibition of HIV replication can reduce viral load. Such antiretroviral therapy typically involves combinations of drugs such as protease inhibitors, nucleoside analogs, and non-nucleoside reverse transcriptase inhibitors. Other agents, including biologics, have also demonstrated some antiviral effects. The decrease in viral load is generally, but not always, associated with an increase in the number of circulating CD4.sup.+ T-cells. (Yarchoan et al., Ann Intern. Med. 115:184-89, 1991; Hirsch and D'Aquila, N. Engl. J. Med. 328:1686-95, 1993; Volberding, P. A., In: Crowe et al., eds., Management of the HIV-Infected Patient, pp. 53-63). Unfortunately, antiretroviral drugs do not result in complete reconstitution of the immune function. Moreover, inhibition of viral replication by these agents is temporary, due to the evolution of resistant strains of virus that can grow in the presence of the antiretroviral agents. (Cameroni et al., Third Human Retroviral Conference, January 1996, Abstract #LB6a).
Growth factor cytokines such as granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and erythropoietin (EPO) have also been administered to patients with HIV. (Scadden et al., 1991, Levine et al., Blood 73:3148-54, 1991; Kaplan et al., J. Clin. Oncol. 9:929-40, 1991; Stricken and Goldberg, Clin. Immunol. Immunopathol. 79:194-96, 1996; Miles et al., Blood 77:2109-17, 1991; Pluda et al., Hematol. Oncol. Clin. North Am. 5:22948, 1991). Recently, GM-CSF has been the subject of several studies to evaluate its ability to prevent opportunistic infections in individuals with HIV.
LEUKINE.RTM., a yeast-derived form of GM-CSF, is currently available for use in promoting myeloid cell recovery following bone marrow transplant post-myeloablative therapy for the treatment of malignancies. An E. coli-derived form of GM-CSF is also available for use in promoting the recovery of neutrophils in HIV-infected patients with granulocytopenia. (Scadden et al., J. Clin. Oncol. 9:802-08, 1991; Levine et al., Blood 78:3148-54, 1991; Kaplan et al., J. Clin. Oncol. 9:929-40, 1991; Hardy et al., Eur. J. Clin. Microbiol. Infect. Dis. 13:S34-S40, 1994). However, the widespread use of GM-CSF for treatment of HIV infection has been hindered by data from in vitro studies whose results suggest that this cytokine might actually enhance HIV replication (Bender et al., J. Immunol. 151:5416, 1993; Foli et al., Blood 8:2114, 1995; Pluda et al., Hematol. Oncol. Clin. North Am. 5:229-48, 1991). More recent studies have reported results which are inconsistent with earlier studies with regard to the effect of GM-CSF on HIV viral replication (Perno et al., Third Human Retroviral Conf., January 1996, Abstract #463; Pluda et al., Blood 76:463-72, 1990; Fletcher and Gasson, Blood 71:652-58, 1988; Mitsuyasu, R. T. In: Volberding and Jacobson, eds. AIDS Clinical Review, N.Y., N.Y. 1993-94, pp. 189-212). It is now believed that in the presence of antiretroviral therapy, GM-CSF does not increase HIV viral replication. (Scadden et al., 1995; Davison et al., J. Clin. Pathol. 47:855-57, 1994, Scadden et al., AIDS Res. and Human Retroviruses 12:1151-59, 1996). Indeed, in vitro data have demonstrated the enhancement of AZT activity by GM-CSF due to increased intracellular concentration of the active triphosphorylated form of AZT. (Hammer and Gillis, Antimicrob. Agents Chemother. 31:1046-50, 1987).
Developing effective therapies for HIV disease has presented a formidable challenge for medical researchers. Although significant advancements have been made in the treatment of HIV-infected patients, many patients remain untreatable due to ineffectiveness of the therapeutic drugs used or inability of the patients to tolerate the side effects of the therapies. Clearly, existing therapies do not yet offer a cure to HIV disease. Immune-modulating agents, such as GM-CSF, may therefore offer an additional alternative treatment.